Mesothelioma is a tumor that occurs in the mesothelium that covers the surface of the pleura, peritoneum and pericardium that respectively envelop the organs of the chest cavity such as the lungs and heart, and abdominal organs such as the digestive tract and liver. In the case of diffuse pleural mesothelioma, chest pain is caused by invasion of the intercostals nerves on the side of the chest wall pleura, and respiratory and circulatory disorders may occur due to tumor growth and accumulation of pleural fluid in the pleura on the organ side (Takagi, Journal of Clinical and Experimental Medicine, (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999). There is eventually proliferation into the adjacent mediastinal organs, progressing to direct invasion of the heart or development into the abdominal cavity by means of the diaphragm, or there may be development outside the chest cavity as a result of additional lymphatic or circulatory metastasis (ibid).
In the U.S., diffuse pleural mesothelioma is reported to occur in 3,000 persons annually, the number of cases began to increase prominently in the 1980s, and is frequently observed in men in their sixties, with the incidence in men being roughly five times that in women (Takagi, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999). According to recent reports in the U.S. and Europe, the incidence of mesothelioma is demonstrating a rapidly increasing trend, and based on epidemiological statistics from the U.K. in 1995, the number of deaths from mesothelioma is predicted to continue to increase over the next 25 years, and in the worst possible scenario, has been indicated as having a risk to the extent of accounting for 1% of all deaths among men born in the 1940s (Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999).
Numerous different classifications of the clinical disease stages have been used for mesothelioma, and since the methods for classifying the disease stage used differ, previous therapeutic reports on mesothelioma have encountered difficulties when comparing the results of treatment (Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999). An international TNM classification for malignant pleural mesothelioma in 1995 by the International Mesothelioma Interest Group (IMIG) (Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999).
In addition, malignant mesothelioma has a causative relationship with exposure to asbestos, and this has also been demonstrated in animal experiments (Tada, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 406-408, 1999). Asbestos that has been inhaled into the respiratory tract reaches a location directly beneath the pleura where a tumor eventually develops due to chronic irritation for at least about 20 years, and this tumor spreads in a thin layer over the entire surface of the pleura (Takagi, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999). Consequently, although malignant mesothelioma is classified as an asbestos-related disease, not all malignant mesothelioma is caused by asbestos, and well-documented exposure is only observed in about half of all patients (Tada, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 406-408, 1999).
Malignant pleural mesothelioma is resistant to treatment, is associated with an extremely poor prognosis, and requires that countermeasures be taken immediately (Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999). For example, although the folic acid antagonist, methotrexate (MTX), has a satisfactory efficacy rate of 37% in large-dose single treatment in combination with leucovin, its use has not proliferated due to the technical difficulty associated with application to mesothelioma that causes retention of a large amount of pleural fluid (Nakano, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 570-573, 2003). In addition, although pleuropulmonary excision and pleurectomy are performed for diffuse pleural mesothelioma, there is increased susceptibility to relapse following treatment, and the post-surgical local relapse rate in particular is high at 35-43% (Takagi, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999).
Numerous human mesothelioma cell lines and several mouse mesothelioma cell lines are known to express IL-6 in vitro, and in mice transplanted with mouse mesothelioma cell line AB22, which expresses a high level of IL-6, IL-6 has been reported to be detected in serum prior to cancer cell growth, clinical symptoms and changes in peripheral blood lymphocyte tissue (Bielefeldt-Ohmann, Cancer Immunol. Immunother. 40: 241-250, 1995). In addition, serum IL-6 levels in patients with malignant pleural mesothelioma are higher in comparison with pulmonary adenoma patients complicated with pleural effusion, and with respect to thrombocytosis, which is one of the clinical symptoms of malignant pleural mesothelioma, there is known to be a remarkable correlation between serum IL-6 levels and platelet counts (Nakano, British Journal of Cancer 77(6): 907-912, 1998). Moreover, the tumor cells of pleural mesothelioma patients express high levels of IL-6, and IL-6 levels in the serum have been reported to increase prior to death (Higashihara, Cancer, Oct. 15, 1992, Vol. 70, No. 8, pp. 2105-2108).
As a result of administering rat anti-mouse IL-6 antibody (6B4) to mouse transplanted with AB22 at the rate of twice a week, Bielefeldt-Ohmann, et al. reported that effects were observed that considerably diminished the onset and progression of clinical symptoms (Bielefeldt-Ohmann, Cancer Immunol. Immunother. 40: 241-250, 1995). However, according to a report by Bielefeldt, anti-IL-6 antibody does not have a direct growth inhibitory effect on AB22 in vitro, there were no differences observed in the postmortem appearances of mice treated with anti-IL-6 antibody and those not treated with said antibody, and tumor masses of considerable size were observed even in the treated mice (Bielefeldt-Ohmann, Cancer Immunol. Immunother. 40: 241-250, 1995). Namely, growth inhibition of mesothelioma by anti-IL-6 antibody has not been known both in vitro and in vivo.
Takagi, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 469-472, 1999
Nakano, Respiration, Vol. 18, No. 9, pp. 916-925, 1999
Tada, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 406-408, 1999
Nakano, Journal of Clinical and Experimental Medicine (March Supplement), “Respiratory Diseases”, pp. 570-573, 2003
Bielefeldt-Ohmann, Cancer Immunol. Immunother. 40: 241-250, 1995
Higashihara, Cancer, Oct. 15, 1992, Vol. 70, No. 8, pp. 2105-2108